Several processes for the preparation of risperidone of the Formula I are disclosed in HU-P 195,793 and the corresponding EP-P 196,132. According to one of said processes a reactive derivative of the general Formula
(wherein W is a reactive group e.g. halogen or an O-sulfonic acid ester group) is reacted in an inert solvent with a benzisoxazol derivative of the Formula

The disadvantage of said process is that the benzisoxazol derivative of the Formula IV is prepared by boiling the corresponding piperidine oxime derivative of the Formula
in a strongly alkaline medium and in the course of this reaction not only the desired fluorine atom in the ortho-position reacts but—according to our experiments—the fluorine atom in the para-position takes also part in the reaction at a rate of about 5%, to yield the dimer of the Formula

As shown in comparative Example 1 said dimer of the Formula VI contaminates the desired benzisoxazol derivative of the Formula IV. The dimer of the Formula VI is significantly less soluble than the benzisoxazol of the Formula IV and therefore practically it cannot be removed by recrystallization. Consequently, on converting the benzisoxazol derivative of the Formula IV contaminated with the dimer of the Formula VI to risperidone, said end-product contains about 3% of the impurity dimer of the Formula

Since the dimer of the Formula VII is much less soluble than risperidone, it is practically impossible to remove the dimer of the Formula VII from risperidone. This is clearly shown in comparative Example 2.
According to another known process risperidone is prepared by reacting the amine of the Formula
with a diketone of the general Formula
(wherein L is a leaving group). However, the preparation of the diketone of the Formula IX is neither described in the prior art citation nor is it exemplified and therefore this process is but of theoretical importance.
According to a further known process a compound of the general Formula
(wherein L1 is a leaving group) is reacted with a piperidine derivative of the general Formula
(wherein L is a leaving group). The prior art lacks an enabling disclosure and for this reason the skilled art worker is not in the position to carry out said process.
ES-P 2,050,069 aims to overcome the disadvantages of the known procedures. According to said Spanish patent a reactive derivative of the general Formula III is reacted with the ketone of the Formula
whereupon the piperidone derivative of the Formula
formed is reacted with hydroxylamine and finally the oxime of the Formula
thus obtained is subjected to cyclization in an inert solvent in the presence of a base. Cyclization which leads to risperidone is carried out either in water in the presence of an alkali hydroxide, alkali carbonate or alkali hydrogencarbonate, or is performed in tetrahydrofuran or dioxan in the presence of an alkali hydride or alkali alkoxide. Ring-closure is preferably carried out in aqueous medium, advantageously at the boiling point of the reaction mixture.
The advantage of this process is that the formation of the dimer of the Formula VII is eliminated. However, this process is accompanied by a very serious draw-back because the piperidone derivative of the Formula XIII formed in the synthesis can be purified only in a very complicated manner either by means of chromatography or via the poorly crystallizable hydrochloride. This has the consequence that the piperidone derivative is obtained only in relatively low yields. According to ES-P 2,050,069 the yield is only 63.1%. Moreover, we failed to reproduce the process with such yields because according to our experiments the yield of the hydrochloride of the piperidone derivative of the Formula XIII is below 60%. According to ES-P 2,050,069 the conversion of the piperidone derivative of the Formula XIII into the corresponding oxime of the Formula II is carried out with a yield of 76.2%. We have succeeded in reproducing the process according to ES-P 2,050,069 only with a yield of about 63%. According to ES-P 2,050,069 the yield of the cyclization of the oxime of the Formula II to risperidone is 79-85%, but we could reproduce only a yield of about 75%. Thus the process disclosed in the Spanish patent is not economical either. The aforesaid is illustrated by comparative Example 3.